Adverse drug reactions (ADRs) remain a major problem in both medical practice and pharmaceutical industry. Among the many types of ADRs, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity syndrome (HSS) are the most serious and life-threatening conditions with SJS and TEN still carry 10-50% mortality rate. See, Roujeau et al., New Engl. J. Med. 333:1600-1607 (1995). Although the incidence of SJS/TEN/HSS is low, these conditions can kill or severely disable previously otherwise healthy people. For the pharmaceutical industry, occurrence of severe drug hypersensitivity can be detrimental; a few cases have prompted the withdrawal of newly released drugs from the market. See the world wide web at fda.gov/safety/recalls/default.htm.
Certain class I HLA alleles (e.g., HLA-A and HLA-B alleles) and certain class II HLA alleles (e.g., HLA-DR alleles) have been found to be associated with ADRs. See, Chung et al., Nature. 428:486 (2004); Hung et al., Proc. Natl. Acad. Sci. U.S.A. 102:4134-4139 (2005); Chessman et al., Immunity. 28, 822-832 (2008); Daly et al., Nat. Genet. 41:816-819 (2009); Singer et al., Nat. Genet. 42:711-714 (2010); Mallal et al., New Engl. J. Med. 358:568-579 (208); Romano et al., Ann. Allergy Asthma. Immunol. 80: 433-437 (1998); Kim et al., Clin. Exp. Allergy 35:339-344 (2005); Flung et al., Pharmacogenet. Genomics 16: 297-306 (2006); Dettling et al., Pharmacogenomics J. 7: 325-332 (2007); O'Donohue et al., Gut 47:717-720 (2000); Lonjou et al., Pharmacogenet. Genomics 18: 99-107 (2008); Kim et al., Pharmacogenomics 11: 879-884(2010); Martin et al., AIDS 19: 97-99 (2005); Littera et al., AIDS 20: 1624-1626 (2006): Locharernkul et al., Epilepsia 49:2087-2091 (2008); and Kindmark et al., Pharmacogenomics J. 8: 186-195 (2008). All of these ADR-HLA allele associations were determined in patients suffering from an ADR induced by an approved drug. At present, there is no method that can be used to predict whether a candidate drug under development will develop these life-threatening conditions, such as SJS/TEN/HSS in human.
As development of a new drug can cost on average 1 billion dollars and 10 years of time, it would be of tremendous value to develop a screening method useful in predicting the safety profile of a candidate drugs at an early stage of drug development.